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Title
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Opposing effects of HLA class I molecules in tuning autoreactive T cells in multiple sclerosis
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Author
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Abstract
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| The major known genetic risk factors in multiple sclerosis reside in the major histocompatibility complex (MHC) region. Although there is strong evidence implicating MHC class II alleles and CD4+ T cells in multiple sclerosis pathogenesis, possible contributions from MHC class I genes and CD8+ T cells are controversial. We have generated humanized mice expressing the multiple sclerosisassociated MHC class I alleles HLA-A*0301 (encoding human leukocyte antigen-A3 (HLA-A3)) and HLA-A*0201 (encoding HLA-A2) and a myelin-specific autoreactive T cell receptor (TCR) derived from a CD8+ T cell clone from an individual with multiple sclerosis to study mechanisms of disease susceptibility. We demonstrate roles for HLA-A3restricted CD8+ T cells in induction of multiple sclerosislike disease and for CD4+ T cells in its progression, and we also define a possible mechanism for HLA-A*0201mediated protection. To our knowledge, these data provide the first direct evidence incriminating MHC class I genes and CD8+ T cells in the pathogenesis of human multiple sclerosis and reveal a network of MHC interactions that shape the risk of multiple sclerosis. |
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Language
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English
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Source (journal)
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Nature medicine. - London, 1995, currens
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Publication
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London
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2008
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ISSN
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1078-8956
[print]
1546-170X
[online]
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DOI
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10.1038/NM.1881
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Volume/pages
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14
:11
(2008)
, p. 1227-1235
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ISI
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000260751200042
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Full text (Publisher's DOI)
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